Intra-patient Dose Escalation Study to Investigate Safety and Feasibility of Vactosertib in Treating Anemic MPN Patients

November 16, 2023 updated by: Weill Medical College of Cornell University

A 2-tiered, Phase 2, Rule-based, Intra-patient Dose Escalation Study to Investigate Safety and Feasibility of Vactosertib (TEW-7197) in the Treatment of Anemic Patients With Philadelphia Chromosome-negative MPNs (Ph-neg MPNs)

This study assesses the potential of using a TGFβ receptor inhibitor for the treatment of anemic patients with myeloproliferative neoplasms. TGFβ signaling is known to be abnormally high in patients with myeloproliferative neoplasms and it is thought that abnormal TGFβ signals cause many of the problems with blood cell formation in these diseases. The study design allows all patients to receive the study drug, vactosertib. The dose of vactosertib is individualized within a pre-set range based upon its effectiveness and tolerability. A total of up to 37 patients will be treated.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

This is a two-tiered multi arm Phase 2 trial of vactosertib (TEW-7197) for the treatment of anemia in Ph-neg MPNs. Both tiers use a rule-based, accelerated dose escalation scheme to efficiently assess the potential of vactosertib to safely and effectively treat anemic patients with Ph-neg MPNs. The first tier of this trial (Tier 1) is an intra-patient dose finding study in 12 patients that uses a low starting dose of vactosertib for all patients. Treatment dose is escalated according to prospectively-defined rules, and a toxicity and treatment effect algorithm during the period of 16 weeks (4 treatment cycles). If pre-established efficacy and safety endpoints are met, then Tier 1 of the study will be followed by a Tier 2 expansion study with an additional 25 patients for a period of 24 weeks (6 treatment cycles).

Vactosertib will be administered concurrently with the patient's current treatment (if any). Prior to enrollment, patients must be on a stable dose of their current therapy for 3 months prior to entering the study. Supportive care measures including packed red blood cell (PRBC) transfusions for HGB <7g/dL, or symptomatic anemia, will be permitted. Administration of erythropoiesis stimulating agents (ESAs), however, will not be permitted on the trial (patients recruited would have serum EPO >125 U/L above which the benefit of ESAs is not supported).

Study Type

Interventional

Enrollment (Estimated)

37

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • New York
      • New York, New York, United States, 10021
        • Recruiting
        • Weill Medical College of Cornell University
        • Contact:
        • Contact:
          • Penina Stewart
          • Phone Number: 646-962-4528

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

Patients who meet the WHO 2016 criteria for a Ph-neg MPN (including PV, ET, MF, MDS/MPN, MPN-U).

  • Patients with MF must have DIPSS+ Intermediate or High-risk MF (primary of post-PV/ET).
  • For patients receiving cytoreductive therapy, they should be on a stable dose of current cytoreductive therapy for at least 3 months prior to C1D1.
  • Anemia as defined by HGB < 10 g/dL, or transfusion of ≥ 2 packed red blood cell (PRBC) unit within the past 4 weeks with HGB ≤8.5g/dL.

  • Ineligible, unsuitable or refractoriness to ESA therapy defined as any of the following:

    • Serum erythropoietin (EPO) >125 U/L.
    • Proven ESA unsuitability is defined by history of any of the following:
    • Loss of erythroid hematologic improvement while receiving stable or increased ESA dose; or
    • ESA-attributed toxicity that, in the treating physician's opinion, makes ESA therapy unsuitable for subject.
    • ESA refractoriness defined by lack of erythroid hematologic improvement to ESA:27
    • Less than 1.5 g/dL increase in hemoglobin after at least 6 weeks of ESA therapy; or
    • Ongoing transfusion dependence that has not been reduced by > 4U over an 8-week period compared to ESA pre-treatment 8 weeks.
  • Acceptable Cardiovascular status

Exclusion Criteria:

  • Any other serious medical condition which in the Investigator's opinion would preclude safe participation in the study.
  • Patients with history of TIA or stroke within the past 12 months are excluded.
  • Female subjects who are breastfeeding, or intend to breastfeed, during the study or in the 30 days following the last dose of study drug are excluded.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Treatment arm
Vactosertib intra-patient dose finding cohort.
Drug: Vactosertib
This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs.
Other Names:
  • TEW-7197

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of adverse events
Time Frame: 16 weeks
To establish a safe and tolerable dose and schedule of vactosertib in Philadelphia chromosome negative Myeloproliferative Neoplasms by recording all adverse events in patients receiving any dose of the drug. All adverse events will be documented accurately regardless of relationship to the study drug. The investigators will assess each adverse event and determine relatedness to study drug.
16 weeks
Change in symptoms of the disease while taking vactosertib
Time Frame: From baseline through 40 weeks
To assess the efficacy of vactosertib in treating anemic patients with Philadelphia chromosome negative Myeloproliferative Neoplasms by measuring symptomatic response. Symptomatic responses will be recorded as the change in scores on the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF-TSS) from baseline through to the end of study. The MPN-SAF-TSS is a questionnaire with questions related to different symptoms that are graded from 0 (not present) through 10 (worst imaginable). The scores are calculated by adding the score for each question at each time the questionnaire is completed. All scores will be compared to the score that was calculated at baseline to determine if there was a symptom response. A symptom response is defined as a change in score by more than 50% decrease from baseline.
From baseline through 40 weeks
Change in spleen size while taking vactosertib
Time Frame: From baseline through 40 weeks
To assess efficacy of vactosertib in treating anemic patients with Philadelphia chromosome negative Myeloproliferative Neoplasms by measuring splenic response. Splenic response will be measured by the change from baseline in spleen volume on a sonogram of the upper left quadrant (at the end of Tier treatment) and in the change from baseline of the spleen length measured by palpation (at each visit until the end of study).
From baseline through 40 weeks
Change in transfusion dependency while taking vactosertib
Time Frame: From baseline through 40 weeks
To assess efficacy of vactosertib in treating anemic patients with Philadelphia chromosome negative Myeloproliferative Neoplasms by measuring erythropoietic response. Erythropoietic response will be measured by the change from baseline of transfusion dependency.This will be measured by comparing the number of transfusions a subject required in the 8 weeks prior to beginning therapy to the number of transfusions required while on study.
From baseline through 40 weeks
Change in hemoglobin values while taking vactosertib
Time Frame: From baseline through 40 weeks
To assess efficacy of vactosertib in treating anemic patients with Philadelphia chromosome negative Myeloproliferative Neoplasms by measuring erythropoietic response. Erythropoietic response will be measured by the change in hemoglobin values from baseline. This will be measured by obtaining Complete Blood Counts (CBC) at every study visit.
From baseline through 40 weeks
Change in EPO levels while taking vactosertib
Time Frame: From baseline through 40 weeks
To assess efficacy of vactosertib in treating anemic patients with Philadelphia chromosome negative Myeloproliferative Neoplasms by measuring erythropoietic response. Erythropoietic response will be measured by the change in EPO levels from baseline. Serum EPO levels will be measured on day 1 of each cycle.
From baseline through 40 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in MPN driver mutation ratios in patients taking vactosertib
Time Frame: From baseline through 40 weeks
To evaluate the on target molecular activity of vactosertib in anemic patients with Philadelphia negative Myeloproliferative Neoplasms. This will be determined by measuring the change in blood (and/or marrow) allelic ratio of MPN driver mutations (JAK2, CALR or MPL).
From baseline through 40 weeks
Histologic change in the bone marrow
Time Frame: From baseline through 40 weeks
To evaluate the on target molecular activity of vactosertib in anemic patients with Philadelphia negative Myeloproliferative Neoplasms. This will be measured by the histologic response patients have to vactosertib. Histologic response will be measured by change in bone marrow biopsy cellularity and fibrosis grade.
From baseline through 40 weeks
Change in Molecular activity of vactosertib
Time Frame: From baseline through 40 weeks
To evaluate the on target molecular activity of vactosertib in anemic patients with Philadelphia negative Myeloproliferative Neoplasms. This will be measured by looking at the SMAD2/3 phosphorylation measured by flow cytometry of peripheral blood and/or bone marrow hematopoietic cells or by immunohistochemical staining of bone marrow biopsy sections.
From baseline through 40 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Weill Medical College of Cornell University

Investigators

  • Principal Investigator: Joseph M Scandura, MD, PhD, Weill Medical College of Cornell University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 22, 2019

Primary Completion (Estimated)

September 1, 2024

Study Completion (Estimated)

September 1, 2025

Study Registration Dates

First Submitted

September 18, 2019

First Submitted That Met QC Criteria

September 23, 2019

First Posted (Actual)

September 25, 2019

Study Record Updates

Last Update Posted (Estimated)

November 21, 2023

Last Update Submitted That Met QC Criteria

November 16, 2023

Last Verified

November 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 19-06020285

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Myeloproliferative Neoplasm

Clinical Trials on Vactosertib

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Saudi Arabia

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe